Memory-related Mild Cognitive Impairment May Be Linked to More Severe Alpha-Synuclein Buildup, Researchers Say

Alpha-Synuclein Buildup

Memory-related mild cognitive impairment in Parkinson’s disease may be associated with a more severe buildup of alpha-synuclein protein in the brain — such as that observed in more advanced stages of the disease, a study finds.

The results of the study, “Neuropathological Findings in Parkinson’s Disease With Mild Cognitive Impairment,” were published in Movement Disorders.

Studying neuropathological markers — meaning the molecular, cellular, or tissue abnormalities characteristic in a given disease — in people with neurological disorders like Parkinson’s allows doctors and scientists to better understand the different tissue changes that contribute to the disease mechanism of a given disorder.

Parkinson’s is a multisystem neurodegenerative disorder with motor and non-motor features caused by the selective death of midbrain dopamine-producing neurons. These nerve cells die because of the aggregation, or clumping together, of a protein called alpha-synuclein in structures commonly known as Lewy bodies. Alpha-synuclein is associated with the regulation of the release of dopamine, the neurotransmitter involved in controlling the start and stop of voluntary and involuntary movements.

Although cognitive impairment is one of the most common non-motor complications of Parkinson’s, not much is known about the molecular and brain abnormalities that characterize it. The studies that do exist indicate that Lewy body protein aggregates coexist with amyloid plaques, neurofibrillary tangles, and inflammation — all of which are also observed in Alzheimer’s disease.

To bridge this knowledge gap, a group of researchers now sought to determine the molecular, cellular, and tissue features that underlie Parkinson’s disease with mild cognitive impairment. The work was a collaboration between the Mayo Clinic in Arizona, the Barrow Neurological Institute, also in Arizona, the Banner Sun Health Research Institute in Arizona, the Cleveland Clinic in Ohio, and the University of California-Davis. The team used autopsy data from the Arizona Study of Aging and Neurodegenerative Disorders.

The scientists compared brain tissue abnormalities of people with amnestic mild cognitive impairment (MCI) with those of patients with non-amnestic MCI. Amnestic MCI is a type of mild cognitive impairment that primarily affects memory, while non-amnestic MCI affects thinking skills other than memory, including the ability to make decisions or visual perception.

Out of 736 screened individuals, 159 had pathologically defined Parkinson’s disease. Of these, only 25 — eight women and 17 men, ages 69-92 — had concurrent mild cognitive impairment. A total of 14 (56%) autopsied subjects had amnestic MCI while 11 (44%) had non-amnestic MCI.

The results revealed that each individual with Parkinson’s disease with mild cognitive impairment had significantly distinct molecular and tissue abnormalities from every other study subject with an identical diagnosis. Consequently, the scientists found no specific set of molecular, cellular, or tissue changes that they could reliably allocate to cognitive impairment in Parkinson’s.

Alpha-synuclein accumulation was more severe in some cases than others, and there were Alzheimer’s disease-related features — including neuritic plaques, neurodegeneration of cerebral white matter, and cerebral amyloid angiopathy, or amyloid buildup on the walls of brain arteries — in these patients’ brain samples. The scientists also observed that patients had a specific genetic variant of the apolipoprotein (APOE) gene, called APOE4, the most prevalent genetic risk factor for Alzheimer’s disease.

Importantly, non-amnestic patients had a significant increase in the severity of Lewy body pathology, or alpha-synuclein buildup, compared with amnestic subjects — 63% versus 21%.

The scientist note that there are apparently distinct biological mechanisms between Alzheimer’s and Parkinson’s disease. However, these neurodegenerative disorders seem to overlap to some extent.

While this is a relatively small study, the findings suggest that despite significant heterogeneity in cellular and tissue abnormalities, Parkinson’s patients with amnestic mild cognitive impairment might be more prone to greater alpha-synuclein accumulation.

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Cellular Location of Neuroprotective Protein Associated with Parkinson’s Disease Development, Study Finds

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Toxic protein aggregates called Lewy bodies sequestrate a protein that is usually found in the cell nucleus and known to protect against neurodegeneration, and change in this protein’s location contributes to the mechanisms underlying Parkinson’s disease, researchers report.

The study, “Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson’s disease patients,” was published in Neuroscience Letters.

Aging is a primary risk factor for Parkinson’s disease as age-related changes in cellular function predispose people to the development of this neurodegenerative disorder.

Evidence suggests a close relationship between neuronal death and toxic protein inclusions, such as Lewy bodies — clumps of alpha-synuclein protein. However, the exact mechanism of how these aggregates result in disease remains to be understood.

“It has been reported that repressor element-1 silencing transcription factor, (also known as) neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes,” the researchers wrote.

Studies have shown that REST expression is decreased in Alzheimer’s disease, but little is known about its role in Parkinson’s disease.

Therefore, researchers from Juntendo University in Japan set to identify the neuroprotective functions of REST in aging and the brains of Parkinson’s disease patients.

The team used post-mortem brain samples of normal aging people (controls), and Parkinson’s or dementia with Lewy bodies patients, and looked at different areas to determine where REST was located within neurons.

In a normal aging (more than 72 years old) brain, REST was present in the nucleus and cytosol (the fluid found inside cells) of dopaminergic neurons present in the substantia nigra — a midbrain area important for muscle control.

This was not the case in the middle-aged brains (age 47 and 61 years), where REST was not observed in the nucleus, and there was a small amount of cytosolic accumulation, suggesting that nuclear entry of REST is dependent on the cellular aging process.

In contrast to healthy controls, REST expression was decreased in patients with Parkinson’s disease and dementia with Lewy bodies, both in the nucleus and cytosol of dopaminergic substantia nigra neurons and cortical neurons. Instead, REST was strongly detected within Lewy bodies.

To dissemble dysfunctional proteins, neurons use two major cellular pathways: the ubiquitin-proteasome system, where short-lived proteins in the cytoplasm and nucleus are degraded by a complex called the proteasome; and the autophagy-lysosome pathway, which digests long-lived proteins and abnormal cellular structures, including mitochondria, the cell’s powerhouse.

The proteasome is a tiny, barrel-shaped cellular structure that degrades toxic non-functional proteins that have been molecularly tagged for destruction.

Disease-related protein aggregates contain ubiquitinated proteins (proteins that have been “tagged” for degradation), and p62 — a molecular receptor that recognizes and shuttles ubiquitinated proteins for degradation.

Researchers wanted to understand whether REST interacted with ubiquitinated protein aggregates. Therefore, they investigated the transcription factor’s location in mouse brain cells that were either normal or were genetically engineered to lack the ability to perform protein degradation (autophagy) specifically in dopaminergic neurons.

In the substantia nigra of normal aging healthy mice (12 months of age), there was no detectable interaction between REST and p62, while in animals with a dysfunctional protein degradation pathway, REST was found in p62-positive aggregates within the cytoplasm. This suggests that REST is incorporated into cytoplasmic aggregates that accumulate as a consequence of autophagy dysfunction.

Therefore, REST aggregating with p62 suggests that it is part of a lesion associated with Lewy body formation.

Scientists then tested if the accumulation of ubiquitinated proteins induced REST gene expression in a human neuroblastoma (a rare type of cancer affecting the nervous system) cell line. Results showed that REST accumulated (was not degraded) in the presence of an autophagy inhibitor called MG132 — which blocks neuronal molecule-degradation systems. However, REST did not accumulate upon the addition of a proteasome-specific inhibitor, called lactacystin, which indicates that REST is dissembled via the autophagy-lysosome pathway.

When researchers added rotenone (a pesticide that inhibits the function of mitochondria) to neurons, REST accumulation increased.

“As rotenone is a possible Parkinson-causing agent, loss of neuronal REST accumulation in aged-neurons may relate to the PD pathology (the typical behaviour of a disease),” the researchers said.

Nuclear accumulation of REST “occurs as a normal aging process and Lewy pathology disturbs the process in dopaminergic neurons by sequestering REST. The alteration of neuronal aging processes including the loss of REST in neurons may associate with the PD pathogenesis,” they concluded.

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4 Possible Causes of Parkinson’s Disease

While the exact cause of Parkinson’s disease is currently unknown, scientists have come up with four possible theories according to the Mayo Clinic.

1. Genetics
There are certain genes which, when they become mutated, cause Parkinson’s disease. However, these mutated genes are very rare, except in cases where Parkinson’s runs in the family. There are also some gene variations which seem to slightly increase the risk of developing Parkinson’s.

MORE: Seven ways to help you self-manage Parkinson’s disease

2. Environment
Researchers think that there are some environmental factors and toxins which may trigger Parkinson’s disease, although they feel the increased risk is small.

3. Presence of Lewy bodies
Changes happening within the brain may also be a trigger for Parkinson’s disease. Lewy bodies are proteins found in brain cells which are biomarkers of the disease and may hold the key to finding out the exact cause.

4. Alpha-synuclein in Lewy bodies
There are many different substances found in Lewy bodies, but scientists are focusing on alpha-synuclein proteins. Alpha-synuclein proteins don’t break down; they form clumps in the cells which are thought to contribute to the disease.

MORE: The role of dopamine in the development of Parkinson’s disease

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